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Title:

DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation

Abstract:

The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-4 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.

1. A pharmaceutical composition comprising or made from: (a) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine in a dosage of 2.5 mg or 5 mg, (b) metformin hydrochloride, (c) one or more pharmaceutical excipients, and (d) a basic amino acid having an intramolecular amino group and alkaline characteristics, which basic amino acid is present in an amount sufficient to suppress degradation of said 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine, wherein the pharmaceutical composition is a tablet comprising a film-coat; and wherein the pharmaceutical composition comprises the following amounts (% by weight of total coated tablet mass): 0.1-0.5% of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine, and 47-85% of metformin hydrochloride.

2. The pharmaceutical composition according to claim 1, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine is stabilized against chemical degradation.

3. The pharmaceutical composition according to claim 1, wherein the basic amino acid having an intramolecular amino group and alkaline characteristics is selected from L-arginine, L-lysine and L-histidine.

4. The pharmaceutical composition according to claim 1, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine is present in a dosage strength of 5 mg.

5. The pharmaceutical composition according to claim 1, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine is present in a dosage strength of 2.5 mg.

6. The pharmaceutical composition according to claim 1, wherein metformin hydrochloride is present in a dosage range from about 100 mg to about 1500 mg.

7. The pharmaceutical composition according to claim 6, wherein metformin hydrochloride is present in a dosage strength of 250, 500, 625, 750, 850, or 1000 mg.

8. The pharmaceutical composition according to claim 6, wherein metformin hydrochloride is present in a dosage strength of 500 mg, 850 mg, or 1000 mg.

9. The pharmaceutical composition according to claim 1, wherein the basic amino acid having an intramolecular amino group and alkaline characteristics is L-arginine.

10. The pharmaceutical composition according to claim 9, wherein L-arginine is present from about 1 mg to about 25 mg.

11. The pharmaceutical composition according to claim 9, wherein L-arginine is present from about 1 mg to about 50 mg.

12. The pharmaceutical composition according to claim 9, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine and L-arginine are present in a weight ratio from about 1:20 to about 10:1.

13. The pharmaceutical composition according to claim 9, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine and L-arginine are present in a weight ratio from about 1:15 to about 10:1.

14. The pharmaceutical composition according to claim 9, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine and L-arginine are present in a weight ratio from about 1:10 to about 10:1.

15. The pharmaceutical composition according to claim 1, wherein the excipients are selected from the group consisting of one or more fillers, a binder, a lubricant, and a glidant.

16. The pharmaceutical composition according to claim 1, comprising copovidone as binder.

17. The pharmaceutical composition according to claim 16, further comprising one or more of the following: the filler corn starch, the lubricant magnesium stearate, and the glidant colloidal anhydrous silica.

18. The pharmaceutical composition according to claim 1, wherein the tablet is a mono-layer tablet.

19. The pharmaceutical composition according to claim 1, wherein the film-coat comprises a film-coating agent, a plasticizer, optionally a glidant, and optionally one or more pigments.

20. The pharmaceutical composition according to claim 1, in which the pharmaceutical composition is a mono-layer tablet, wherein one or more of the following applies: the percentage of metformin hydrochloride is about 85% by weight of total tablet core, the percentage of DPP-4 inhibitor is about 0.2%-0.4% by weight of total tablet core, the percentage of L-arginine is about 2% by weight of total tablet core, the tablet crushing strength is higher than or equal 100 N, the tablet friability is lower than or equal 0.5%, the tablet thickness is from about 5.7 to about 8.4 mm, the tablet core weight is from about 590 to about 1180 mg, and the tablet disintegration time is lower than or equal 15 minutes.

21. The pharmaceutical composition according to claim 1, which is an immediate release dosage form, characterized in that in a dissolution test after 45 minutes at least 75% by weight of each of the active ingredients is dissolved.

22. A solid pharmaceutical composition which is a mono-layer tablet comprising: 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine in a dosage of 2.5 mg, metformin hydrochloride, L-arginine in an amount sufficient to suppress degradation of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R- )-amino-piperidin-1-yl)-xanthine, and one or more fillers and one or more binders, wherein the percentage of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine is about 0.2%-0.4% by weight of total tablet core.

23. The solid pharmaceutical composition according to claim 22, further comprising one or more glidants and/or one or more lubricants.

24. The pharmaceutical composition according to claim 1 comprising the active ingredients in a dosage strength of 2.5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine and 500 mg of metformin hydrochloride.

25. The pharmaceutical composition according to claim 1 comprising the active ingredients in a dosage strength of 2.5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine and 850 mg of metformin hydrochloride.

26. The pharmaceutical composition according to claim 1 comprising the active ingredients in a dosage strength of 2.5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine and 1000 mg of metformin hydrochloride.

27. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises the following amount (% by weight of total coated tablet mass): 0.07-2.2% of L-arginine.

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